title: Salinomycin induces cell death via inactivation of Stat3 and downregulation of Skp2.
abstract: Salinomycin has been shown to control breast cancer stem cells, although the mechanisms underlying its anticancer effects are not clear. Deregulation of cell cycle regulators play critical roles in tumorigenesis, and they have been considered as anticancer targets. In this study, we investigated salinomycin effect on cell cycle progression using OVCAR-8 ovarian cancer cell line and multidrug-resistant NCI/ADR-RES and DXR cell lines that are derived from OVCAR-8. Parental OVCAR-8 cells are sensitive to several anticancer drugs, but NCI/ADR-RES and DXR cells are resistant to several anticancer drugs. However, salinomycin caused cell growth inhibition and apoptosis via cell cycle arrest at G1 in all three cell lines. Salinomycin inhibited signal transducer and activator of transcription 3 (Stat3) activity and thus decreased expression of Stat3-target genes, including cyclin D1, Skp2, and survivin. Salinomycin induced degradation of Skp2 and thus accumulated p27Kip1. Knockdown of Skp2 further increased salinomycin-induced G1 arrest, but knockdown of p27Kip1 attenuated salinomycin effect on G1 arrest. Cdh1, an E3 ligase for Skp2, was shifted to nuclear fractions upon salinomycin treatment. Cdh1 knockdown by siRNA reversed salinomycin-induced Skp2 downregulation and p27Kip1 upregulation, indicating that salinomycin activates the APC(Cdh1)-Skp2-p27Kip1 pathway. Concomitantly, si-Cdh1 inhibited salinomycin-induced G1 arrest. Taken together, our data indicate that salinomycin induces cell cycle arrest and apoptosis via downregulation or inactivation of cell cycle-associated oncogenes, such as Stat3, cyclin D1, and Skp2, regardless of multidrug resistance.
authors.affiliation: Comparative Biomedicine Research Branch, Division of Cancer Biology, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: K H
authors.initials: KH
authors.lastname: Koo
authors.forename: H
authors.initials: H
authors.lastname: Kim
authors.forename: Y-K
authors.initials: YK
authors.lastname: Bae
authors.forename: K
authors.initials: K
authors.lastname: Kim
authors.forename: B-K
authors.initials: BK
authors.lastname: Park
authors.forename: C-H
authors.initials: CH
authors.lastname: Lee
authors.forename: Y-N
authors.initials: YN
authors.lastname: Kim
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D059585:G1 Phase Cell Cycle Checkpoints; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D011714:Pyrans / Q000494:pharmacology*; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D000095662:Polyether Polyketides
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011714:Pyrans; D044786:S-Phase Kinase-Associated Proteins; D050796:STAT3 Transcription Factor; C513055:ABCB1 protein, human; C530104:CCND1 protein, human; C436291:CDKN1B protein, human; C494086:STAT3 protein, human; C010327:salinomycin; D000095662:Polyether Polyketides